Abstract 2290: A Genetic Model of Dilated Cardiomyopathy Mediated by Small Vessel Ischemia
Nerve growth factor (NGF) is expressed in many extraneuronal tissues, including the heart, and mediates cell survival by binding to the neurotrophin receptor TrkA. In addition, our lab showed that the secreted, pro-form of NGF (proNGF) triggers apoptosis by binding to the proneurotrophin receptors p75NTR and sortilin. Thus, the balance of NGF/proNGF regulates survival or death. We have generated a knock-in mouse model in which the balance of secreted NGF/proNGF has been altered to favor proNGF in all tissues which normally express NGF. We replaced one allele with uncleavable proNGF, while maintaining the second allele wild-type. Expression of both forms remains under control of the endogenous NGF promoter. These mice, termed NGF+/pro, spontaneously develop progressive dilated cardiomyopathy (DCM). By 2 months of age, NGF+/pro mice exhibit decreased fractional shortening compared with NGF+/+ littermates. Worsening cardiac contractility is accompanied by extensive fibrosis, dilation, and histiocytic infiltration, and is associated with early mortality. We find, using electron microscopy and immunofluorescence techniques, that the cause of DCM in the NGF+/pro mice is an increased activation of microvascular cardiac endothelial cells. The DCM phenotype of NGF+/pro mice is rescued genetically by breeding onto a p75NTR−/− background, confirming the pathogenic role of proNGF - p75NTR signaling.